A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Depakote Warnings, Precautions, Pregnancy, Nursing, Abuse - Divalproex Sodium
Depakote Warnings, Precautions, Pregnancy, Nursing, Abuse - Divalproex Sodium
WARNINGS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients
receiving valproic acid. These incidents usually have occurred during the first
six months of treatment. Serious or fatal hepatotoxicity may be preceded by
non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia,
and vomiting. In patients with epilepsy, a loss of seizure control may also
occur. Patients should be monitored closely for appearance of these symptoms.
Liver function tests should be performed prior to therapy and at frequent intervals
thereafter, especially during the first six months. However, physicians should
not rely totally on serum biochemistry since these tests may not be abnormal
in all instances, but should also consider the results of careful interim medical
history and physical examination.
Caution should be observed when administering DEPAKOTE products
to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants,
children, those with congenital metabolic disorders, those with severe seizure
disorders accompanied by mental retardation, and those with organic brain disease
may be at particular risk. Experience has indicated that children under the
age of two years are at a considerably increased risk of developing fatal hepatotoxicity,
especially those with the aforementioned conditions. When DEPAKOTE is used in
this patient group, it should be used with extreme caution and as a sole agent.
The benefits of therapy should be weighed against the risks. Above this age
group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity
decreases considerably in progressively older patient groups.
The drug should be discontinued immediately in the presence
of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic
dysfunction has progressed in spite of discontinuation of drug.
Pancreatitis
Cases of life-threatening pancreatitis have been reported in
both children and adults receiving valproate. Some of the cases have been described
as hemorrhagic with rapid progression from initial symptoms to death. Some cases
have occurred shortly after initial use as well as after several years of use.
The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge
with valproate. In clinical trials, there were 2 cases of pancreatitis without
alternative etiology in 2416 patients, representing 1044 patient-years experience.
Patients and guardians should be warned that abdominal pain, nausea, vomiting,
and/or anorexia can be symptoms of pancreatitis that require prompt medical
evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.
Alternative treatment for the underlying medical condition should be initiated
as clinically indicated (see BOXED WARNING).
Urea Cycle Disorders (UCD)
Divalproex sodium is contraindicated in patients with known
urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal,has been reported
following initiation of valproate therapy in patients with urea cycle disorders,
a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase
deficiency. Prior to the initiation of valproate therapy, evaluation for UCD
should be considered in the following patients: 1) those with a history of unexplained
encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related
or postpartum encephalopathy, unexplained mental retardation, or history of
elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those
with a family history of UCD or a family history of unexplained infant deaths
(particularly males); 4) those with other signs or symptoms of UCD. Patients
who develop symptoms of unexplained hyperammonemic encephalopathy while receiving
valproate therapy should receive prompt treatment (including discontinuation
of valproate therapy) and be evaluated for underlying urea cycle disorders (see
CONTRAINDICATIONS and PRECAUTIONS).
Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly
patients with dementia (mean age = 83 years), doses were increased by 125 mg/day
to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate
patients had somnolence compared to placebo, and although not statistically
significant, there was a higher proportion of patients with dehydration. Discontinuations
for somnolence were also significantly higher than with placebo. In some patients
with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these
events to have a lower baseline albumin concentration, lower valproate clearance,
and a higher BUN. In elderly patients, dosage should be increased more slowly
and with regular monitoring for fluid and nutritional intake, dehydration, somnolence,
and other adverse events. Dose reductions or discontinuation of valproate should
be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence (see DOSAGE AND ADMINISTRATION).
Thrombocytopenia
The frequency of adverse effects (particularly elevated liver
enzymes and thrombocytopenia [see PRECAUTIONS])
may be dose-related. In a clinical trial of DEPAKOTE as monotherapy in patients
with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on
average, had at least one value of platelets £ 75
x 109/L. Approximately half of these patients had treatment discontinued,
with return of platelet counts to normal. In the remaining patients, platelet
counts normalized with continued treatment. In this study,the probability of
thrombocytopenia appeared to increase significantly at total valproate concentrations
of ³110 µg/mL (females) or ³135
µg/mL (males). The therapeutic benefit which may accompany the higher doses
should therefore be weighed against the possibility of a greater incidence of
adverse effects.
Usage In Pregnancy
ACCORDING TO PUBLISHED AND UNPUBLISHED REPORTS,VALPROIC ACID
MAY PRODUCE TERATOGENIC EFFECTS IN THE OFFSPRING OF HUMAN FEMALES RECEIVING
THE DRUG DURING PREGNANCY.
THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE WHICH
INDICATE THAT THE USE OF ANTIEPILEP-TIC DRUGS DURING PREGNANCY RESULTS IN AN
INCREASED INCIDENCE OF BIRTH DEFECTS IN THE OFFSPRING. ALTHOUGH DATA ARE MORE
EXTENSIVE WITH RESPECT TO TRIMETHADIONE,PARAMETHADIONE,PHENYTOIN,AND PHENOBARBITAL,
REPORTS INDICATE A POSSIBLE SIMILAR ASSOCIATION WITH THE USE OF OTHER ANTIEPILEPTIC
DRUGS. THEREFORE,ANTIEPILEPSY DRUGS SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING
POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF
THEIR SEIZURES.
THE INCIDENCE OF NEURAL TUBE DEFECTS IN THE FETUS MAY BE INCREASED
IN MOTHERS RECEIVING VALPROATE DURING THE FIRST TRIMESTER OF PREGNANCY. THE
CENTERS FOR DISEASE CONTROL (CDC) HAS ESTIMATED THE RISK OF VALPROIC ACID EXPOSED
WOMEN HAVING CHILDREN WITH SPINA BIFIDA TO BE APPROXIMATELY 1 TO 2%.
OTHER CONGENITAL ANOMALIES (EG,CRANIOFACIAL DEFECTS,CARDIOVASCULAR
MALFORMATIONS AND ANOM-ALIES INVOLVING VARIOUS BODY SYSTEMS), COMPATIBLE AND
INCOMPATIBLE WITH LIFE, HAVE BEEN REPORTED. SUFFICIENT DATA TO DETERMINE THE
INCIDENCE OF THESE CONGENITAL ANOMALIES IS NOT AVAILABLE.
THE HIGHER INCIDENCE OF CONGENITAL ANOMALIES IN ANTIEPILEPTIC
DRUG-TREATED WOMEN WITH SEIZURE DISORDERS CANNOT BE REGARDED AS A CAUSE AND
EFFECT RELATIONSHIP. THERE ARE INTRINSIC METHODOLOGIC PROBLEMS IN OBTAINING
ADEQUATE DATA ON DRUG TERATOGENICITY IN HUMANS; GENETIC FACTORS OR THE EPILEPTIC
CONDITION ITSELF, MAY BE MORE IMPORTANT THAN DRUG THERAPY IN CONTRIBUTING TO
CONGENITAL ANOMALIES.
PATIENTS TAKING VALPROATE MAY DEVELOP CLOTTING ABNORMALITIES.
A PATIENT WHO HAD LOW FIBRINOGEN WHEN TAKING MULTIPLE ANTICONVULSANTS INCLUDING
VALPROATE GAVE BIRTH TO AN INFANT WITH AFIBRINOGENEMIA WHO SUBSEQUENTLY DIED
OF HEMORRHAGE. IF VALPROATE IS USED IN PREGNANCY, THE CLOTTING PARAMETERS SHOULD
BE MONITORED CAREFULLY.
HEPATIC FAILURE, RESULTING IN THE DEATH OF A NEWBORN AND OF
AN INFANT, HAVE BEEN REPORTED FOLLOWING THE USE OF VALPROATE DURING PREGNANCY.
Animal studies have demonstrated valproate-induced teratogenicity.
Increased frequencies of malformations, as well as intrauterine growth retardation
and death, have been observed in mice, rats, rabbits, and monkeys following
prenatal exposure to valproate. Malformations of the skeletal system are the
most common structural abnormalities produced in experimental animals, but neural
tube closure defects have been seen in mice exposed to maternal plasma valproate
concentrations exceeding 230 µg/mL (2.3 times the upper limit of the human therapeutic
range) during susceptible periods of embryonic development. Administration of
an oral dose of 200 mg/kg/day or greater (50% of the maximum human daily dose
or greater on a mg/m2 basis) to pregnant rats during organogenesis
produced malformations (skeletal, cardiac, and urogenital) and growth retardation
in the offspring. These doses resulted in peak maternal plasma valproate levels
of approximately 340 µg/mL or greater (3.4 times the upper limit of the human
therapeutic range or greater). Behavioral deficits have been reported in the
offspring of rats given a dose of 200 mg/kg/day throughout most of pregnancy.
An oral dose of 350 mg/kg/day (approximately 2 times the maximum human daily
dose on a mg/m2 basis) produced skeletal and visceral malformations
in rabbits exposed during organogenesis. Skeletal malformations, growth retardation,
and death were observed in rhesus monkeys following administration of an oral
dose of 200 mg/kg/day (equal to the maximum human daily dose on a mg/m2
basis) during organogenesis. This dose resulted in peak maternal plasma
valproate levels of approximately 280 µg/mL (2.8 times the upper limit of the
human therapeutic range).
The prescribing physician will wish to weigh the benefits of
therapy against the risks in treating or counseling women of childbearing potential.
If this drug is used during pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to
the fetus.
Antiepileptic drugs should not be discontinued abruptly in
patients in whom the drug is administered to prevent major seizures because
of the strong possibility of precipitating status epilepticus with attendant
hypoxia and threat to life. In individual cases where the severity and frequency
of the seizure disorder are such that the removal of medication does not pose
a serious threat to the patient, discontinuation of the drug may be considered
prior to and during pregnancy, although it cannot be said with any confidence
that even minor seizures do not pose some hazard to the developing embryo or
fetus.
Tests to detect neural tube and other defects using current
accepted procedures should be considered a part of routine prenatal care in
childbearing women receiving valproate.
PRECAUTIONS
Hepatic Dysfunction
See BOXED WARNING, CONTRAINDICATIONS
and WARNINGS. Pancreatitis See
BOXED WARNING and WARNINGS.
Hyperammonemia
Hyperammonemia has been reported in association with valproate
therapy and may be present despite normal liver function tests. In patients
who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic
encephalopathy should be considered and an ammonia level should be measured.
If ammonia is increased, valproate therapy should be discontinued. Appropriate
interventions for treatment of hyperammonemia should be initiated, and such
patients should undergo investigation for underlying urea cycle disorders (see
CONTRAINDICATIONS and WARNINGS
Urea Cycle Disorders).
Asymptomatic elevations of ammonia are more common and when
present, require close monitoring of plasma ammonia levels. If the elevation
persists, discontinuation of valproate therapy should be considered.
General
Because of reports of thrombocytopenia (see WARNINGS),
inhibition of the secondary phase of platelet aggregation, and abnormal coagulation
parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended
that patients receiving DEPAKOTE be monitored for platelet count and coagulation
parameters prior to planned surgery. In a clinical trial of DEPAKOTE as monotherapy
in patients with epilepsy, 34/126 patients (27%) receiving approximately 50mg/kg/day
on average,had at least one value of platelets £75
x 109/L. Approximately half of these patients had treatment discontinued,
with return of platelet counts to normal. In the remaining patients, platelet
counts normalized with continued treat-ment. In this study, the probability
of thrombocytopenia appeared to increase significantly at total valproate concentrations
of ³110 µg/mL (females) or ³
135 µg/mL (males). Evidence of hemorrhage, bruising, or a disorder of
hemostasis/coagulation is an indication for reduction of the dosage or withdrawal
of therapy.
Since DEPAKOTE may interact with concurrently administered
drugs which are capable of enzyme induction, periodic plasma concentration determinations
of valproate and concomitant drugs are recommended during the early course of
therapy. (See PRECAUTIONS-Drug
Interactions.)
Valproate is partially eliminated in the urine as a keto-metabolite
which may lead to a false interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated
with valproate. The clinical significance of these is unknown.
Suicidal ideation may be a manifestation of certain psychiatric
disorders, and may persist until significant remission of symptoms occurs. Close
supervision of high risk patients should accompany initial drug therapy.
There are in vitro studies that suggest valproate stimulates
the replication of the HIV and CMV viruses under certain experimental conditions.
The clinical consequence, if any, is not known. Additionally, the relevance
of these in vitro findings is uncertain for patients receiving maximally
suppressive antiretroviral therapy. Nevertheless, these data should be borne
in mind when interpreting the results from regular monitoring of the viral load
in HIV infected patients receiving valproate or when following CMV infected
patients clinically.
Information for Patients
Patients and guardians should be warned that abdominal pain,
nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore,
require further medical evaluation promptly.
Patients should be informed of the signs and symptoms associated
with hyperammonemic encephalopathy (see PRECAUTIONS
Hyperammonemia) and be told to inform the prescriber if any of these symptoms
occur.
Since DEPAKOTE products may produce CNS depression, especially
when combined with another CNS depressant (eg, alcohol), patients should be
advised not to engage in hazardous activities, such as driving an automobile
or operating dangerous machinery, until it is known that they do not become
drowsy from the drug.
Since DEPAKOTE has been associated with certain types of birth
defects, female patients of child-bearing age considering the use of DEPAKOTE
should be advised to read the Patient Information
Leaflet, which appears as the last section of the labeling.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Valproic acid was administered orally to Sprague Dawley rats
and ICR (HA/ICR) mice at doses of 80 and 170 mg/kg/day (approximately 10 to
50% of the maximum human daily dose on a mg/m2 basis) for two years.
A variety of neoplasms were observed in both species. The chief findings were
a statistically significant increase in the incidence of subcutaneous fibrosarcomas
in high dose male rats receiving valproic acid and a statistically significant
dose-related trend for benign pulmonary adenomas in male mice receiving val-proic
acid. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial
assay (Ames test), did not produce dominant lethal effects in mice, and did
not increase chromosome aberration frequency in an in vivo cytogenetic
study in rats. Increased frequencies of sister chromatid exchange (SCE) have
been reported in a study of epileptic children taking valproate, but this association
was not observed in another study conducted in adults. There is some evidence
that increased SCE frequencies may be associated with epilepsy. The biological
significance of an increase in SCE frequency is not known.
Fertility
Chronic toxicity studies in juvenile and adult rats and dogs
demonstrated reduced spermatogenesis and testicular atrophy at oral doses of
400 mg/kg/day or greater in rats (approximately equivalent to or greater than
the maximum human daily dose on a mg/m2 basis) and 150 mg/kg/day
or greater in dogs (approximately 1.4 times the maximum human daily dose or
greater on a mg/m2 basis). Segment I fertility studies in rats have
shown doses up to 350 mg/kg/day (approximately equal to the maximum human daily
dose on a mg/m2 basis) for 60 days to have no effect on fertility.
THE EFFECT OF VALPROATE ON TESTICULAR DEVELOPMENT AND ON SPERM PRODUCTION AND
FERTILITY IN HUMANS IS UNKNOWN.
Pregnancy
Pregnancy Category D: See WARNINGS.
Nursing Mothers
Valproate is excreted in breast milk. Concentrations in breast
milk have been reported to be 1-10% of serum concentrations. It is not known
what effect this would have on a nursing infant. Consideration should be given
to discontinuing nursing when divalproex sodium is administered to a nursing
woman.
Pediatric Use
Experience has indicated that pediatric patients under the
age of two years are at a considerably increased risk of developing fatal hepa-totoxicity,
especially those with the aforementioned conditions (see BOXED
WARNING). When DEPAKOTE is used in this patient group, it should be
used with extreme caution and as a sole agent. The benefits of therapy should
be weighed against the risks. Above the age of 2 years, experience in epilepsy
has indicated that the incidence of fatal hepatotoxicity decreases considerably
in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing
drugs, will require larger maintenance doses to attain targeted total and unbound
valproic acid concentrations.
The variability in free fraction limits the clinical usefulness
of monitoring total serum valproic acid concentrations. Interpretation of valproic
acid concentrations in children should include consideration of factors that
affect hepatic metabolism and protein binding.
The safety and effectiveness of DEPAKOTE for the treatment
of acute mania has not been studied in individuals below the age of 18 years.
The safety and effectiveness of DEPAKOTE for the prophylaxis
of migraines has not been studied in individuals below the age of 16 years.
The basic toxicology and pathologic manifestations of valproate
sodium in neonatal (4-day old) and juvenile (14-day old) rats are similar to
those seen in young adult rats. However, additional findings, including renal
alterations in juvenile rats and renal alterations and retinal dysplasia in
neonatal rats, have been reported. These findings occurred at 240 mg/kg/day,
a dosage approximately equivalent to the human maximum recommended daily dose
on a mg/m2 basis. They were not seen at 90 mg/kg, or 40% of the maximum
human daily dose on a mg/m2 basis.
Geriatric Use
No patients above the age of 65 years were enrolled in double-blind
prospective clinical trials of mania associated with bipolar illness. In a case
review study of 583 patients, 72 patients (12%) were greater than 65 years of
age. A higher percentage of patients above 65 years of age reported accidental
injury, infection, pain, somnolence, and tremor. Discontinuation of valproate
was occasionally associated with the latter two events. It is not clear whether
these events indicate additional risk or whether they result from preexisting
medical illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related
somnolence and discontinuation for somnolence (see WARNINGS-Somnolence
in the Elderly). The starting dose should be reduced in these patients,
and dosage reductions or discontinuation should be considered in patients with
excessive somnolence (see DOSAGE AND ADMINISTRATION).
There is insufficient information available to discern the
safety and effectiveness of DEPAKOTE for the prophylaxis of migraines in patients
over 65.
top
